Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in clinical practice.

Safety evaluation of XALKORI is based on more than 1200
patients with ALK-positive metastatic NSCLC who received XALKORI as monotherapy
at a starting oral dose of 250 mg twice daily continuously.

ALK-Positive Metastatic NSCLC-Study 1

The data in Table 3 are derived from 343 patients with
ALK-positive metastatic NSCLC enrolled in a randomized, multicenter,
active-controlled, open-label trial (Study 1). Patients in the XALKORI arm
(n=172) received XALKORI 250 mg orally twice daily until documented disease
progression, intolerance to therapy, or the investigator determined that the
patient was no longer experiencing clinical benefit. A total of 171 patients in
the chemotherapy arm received pemetrexed 500 mg/m² (n=99) or
docetaxel 75 mg/m² (n=72) by intravenous infusion every three weeks
until documented disease progression, intolerance to therapy, or the
investigator determined that the patient was no longer experiencing clinical
benefit. Patients in the chemotherapy arm received pemetrexed unless they had
received pemetrexed as part of first-line or maintenance treatment.

The median duration of study treatment was 7.1 months for
patients who received XALKORI and 2.8 months for patients who received
chemotherapy. Across the 347 patients who were randomized to study treatment
(343 received at least one dose of study treatment), the median age was 50
years; 84% of patients in the XALKORI arm and 87% of patients in the
chemotherapy arm were younger than 65 years. A total of 57% of patients on
XALKORI and 55% of chemotherapy patients were female. Forty-six percent (46%)
of XALKORI-treated and 45% of chemotherapy-treated patients were from Asia.

Dose reductions due to adverse reactions were required in
16% of XALKORI-treated patients. The most frequent adverse reactions that led
to dose reduction in the patients treated with XALKORI were alanine aminotransferase (ALT) elevation (7.6%) including some patients with concurrent
aspartate aminotransferase (AST) elevation, QTc prolongation (2.9%), and
neutropenia (2.3%).

Discontinuation of therapy in XALKORI-treated patients
for adverse reactions was 17.0%. The most frequent adverse reactions that led
to discontinuation in XALKORI-treated patients were ILD (1.7%), ALT and AST
elevation (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%). Tables 3 and 4
summarize common Adverse Reactions and Laboratory Abnormalities in
XALKORI-treated patients.

Table 3: Adverse Reactions Reported at a Higher
Incidence ( ≥ 5% Higher for All Grades or ≥ 2% Higher for Grades 3/4)
with XALKORI than Chemotherapy in Study 1

ALK-positive metastatic
NSCLC-Study 2

The safety analysis population
in Study 2 included 934 patients with ALK-positive metastatic NSCLC who
received XALKORI in a clinical trial. The median duration of treatment was 23
weeks. Dosing interruptions and reductions due to treatment-related adverse
events occurred in 23% and 12% of patients, respectively. The rate of
treatment-related adverse events resulting in permanent discontinuation was 5%.
The most common adverse reactions ( ≥ 25%) included vision disorder (55%),
nausea (51%), vomiting (46%), diarrhea (46%), edema (39%), constipation (38%),
and fatigue (26%).

Based on the Visual Symptom
Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Study 1
reported a higher incidence of visual disturbances compared to patients treated
with chemotherapy. The onset of vision disorders generally started within the
first week of drug administration. The majority of patients on the XALKORI arm
in Study 1 ( > 50%) reported visual disturbances; these visual disturbances
occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had
mild or no impact (scores 0 to 3 out of a maximum score of 10) on daily
activities as captured in a patient questionnaire.

Neuropathy

Neuropathy, most commonly
sensory in nature, occurred in 235 (19%) of 1225 patients. Most events (95%)
were Grade 1 or Grade 2 in severity.

Renal Cysts

Renal cysts occurred in 7 (4%)
patients treated with XALKORI and 1 (1%) patient treated with chemotherapy in
Study 1. The majority of renal cysts in XALKORI-treated patients were complex.
Local cystic invasion beyond the kidney occurred, in some cases with imaging
characteristics suggestive of abscess formation. However, across clinical
trials no renal abscesses were confirmed by microbiology tests.

Drugs Whose Plasma Concentrations May Be Altered By
Crizotinib

Crizotinib inhibits CYP3A both in vitro and in vivo [seeCLINICAL PHARMACOLOGY]. Avoid concomitant use of CYP3A substrates with
narrow therapeutic range, including but not limited to alfentanil,
cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus,
and tacrolimus in patients taking XALKORI. If concomitant use of these CYP3A
substrates with narrow therapeutic range is required in patients taking
XALKORI, dose reductions of the CYP3A substrates may be required due to adverse
reactions.